The capacity to distinguish normal from malignant cells in a consistent and reliable fashion remains an important but often elusive goal for cancer therapy. Aberrant forms of glycosylation been described in numerous human cancers, identifying glycans as an entirely novel class of tumor-associated antigens suitable for specific tumor targeting. While the presence of the sialylated version of the Tn antigen (STn) in normal adult human tissues is extremely rare, STn occurs frequently in various human cancers, and can thus be considered to be a tumor-associated antigen. The presence of STn in tumors is associated with poor prognosis and reduced overall survival; therefore, STn is considered an attractive target for cancer therapy. STn as a target for cancer therapy has been studied in both preclinical and clinical settings to date solely using vaccines. The most advanced clinical candidate was Theratope, which consists of synthetic STn coupled to a KLH carrier. While in mouse studies Theratope immunization induced a potent antibody response that was shown to delay growth of STn-expressing mammary carcinoma cells, the vaccine failed to meet its primary endpoint in a phase III non-stratified clinical trial, although a post-hoc analysis reveale activity in a subset of patients. Importantly however, these investigations have demonstrated the safety and potential therapeutic benefit of targeting STn. To our knowledge no considered effort has been expended to develop other types of therapeutic agents beyond vaccines, such as monoclonal antibodies (mAbs) that target STn and also can be used as companion diagnostics. Sialix is committed to meet this unmet need and has already created a panel of anti-STn mAbs that possess high binding affinity and exquisite specificity toward the STn target in a protein-independent fashion. Importantly, Sialix has recently demonstrated that one of its mAbs is capable of significantly reducing tumor growth in an in vivo orthotopic syngeneic model of murine breast cancer where, strikingly, tumor regression was also observed. During the requested SBIR Phase I funding period Sialix will extend and expand these initial extremely promising studies by performing in vitro assays to i) assess the antibody-dependent cellular cytotoxicity (ADCC) activity of each of the 7 anti-STn antibodies in the panel; ii) evaluate the capacity of the mAbs to be internalized into human tumor cells, revealing the potential for future payload conjugation; and iii) determining their cancer specificity using tissue microarrays. Lastly from analysis of the generated in vitro data, a subset of mAbs will be examined for their anti-tumor activity in an orthotopic model of human breast cancer. The end goal of the Phase I study will be to choose 1-2 mAbs for humanization and additional activities that will comprise a Phase II program toward eventual filing of an IND.
Public Health Relevance Statement:
Public Health Relevance: Sialix, Inc. in this SBIR Phase I application proposes to characterize a number of previously generated mouse monoclonal antibodies that specifically bind to a tumor-associated cell surface sugar molecule. Antibodies will be evaluated for potency and cancer specificity in a number of relevant assays including determining their capacity to limit the growth of human breast cancer tumors in a mouse model. The goal of the project is to choose 1-2 of these antibodies for future "humanization" and studies enabling entrance into clinical trials toward eventual use for cancer therapy.
Project Terms:
Adult; Affect; Affinity; Antibodies; Antibody -dependent cell cytotoxicity; Antibody Formation; Antigens; Antigens, Tumor-Associated, Carbohydrate; base; Binding (Molecular Function); Biological Assay; Breast Cancer Cell; Breast Carcinoma; cancer cell; Cancer Patient; cancer therapy; Carbohydrates; Caring; Carrier Proteins; cell killing; Cell Line; Cell surface; chemotherapeutic agent; Clinical; clinical material; Clinical Trials; Companions; Complement-Dependent Cytotoxicity; Coupled; cytotoxic; Data; Data Analyses; Development; Diagnosis; Diagnostic; Engineering; Enhancing Antibodies; Epitopes; Evaluation; Funding; Future; Generations; Glycopeptides; glycosylation; Goals; Gold; Growth; Human; human tissue; humanized monoclonal antibodies; Immune response; Immunization; Immunotherapy; In Vitro; in vitro Assay; in vivo; Individual; Investigation; Keyhole Limpet Hemocyanin; Killings; Lead; malignant breast neoplasm; Malignant Epithelial Cell; Malignant Neoplasms; manufacturing scale-up; Masks; meetings; member; Modeling; Monoclonal Antibodies; mouse model; Mus; neoplastic cell; New Agents; novel; outcome forecast; Paclitaxel; Patients; Pharmacology and Toxicology; Phase; phase 1 study; Phase I Clinical Trials; Polysaccharides; potency testing; pre-clinical; programs; Proteins; public health relevance; Safety; screening; Series; sialosyl-Tn antigen; Small Business Innovation Research Grant; Specificity; sugar; Therapeutic; Therapeutic Agents; Tissue Microarray; Toxic effect; Treatment Efficacy; tumor; Tumor Antigens; tumor growth; Vaccines; Work
